3-179234230-A-G

Position:

• chr3-179234230-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_006218.4(PIK3CA):​c.3073A>G​(p.Thr1025Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1025S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.85

Genes affected

PIK3CA (HGNC:8975): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. This gene has been found to be oncogenic and has been implicated in cervical cancers. A pseudogene of this gene has been defined on chromosome 22. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a helix (size 9) in uniprot entity PK3CA_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_006218.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-179234231-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2633421.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PIK3CA. . Gene score misZ 5.5986 (greater than the threshold 3.09). Trascript score misZ 6.1406 (greater than threshold 3.09). GenCC has associacion of gene with hereditary breast carcinoma, vascular malformation, Cowden disease, Cowden syndrome 5, CLOVES syndrome, familial ovarian cancer, megalencephaly-capillary malformation-polymicrogyria syndrome, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes.
• PP5: Variant 3-179234230-A-G is Pathogenic according to our data. Variant chr3-179234230-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 45467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIK3CA	NM_006218.4	c.3073A>G	p.Thr1025Ala	missense_variant	21/21	ENST00000263967.4
PIK3CA	XM_006713658.5	c.3073A>G	p.Thr1025Ala	missense_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIK3CA	ENST00000263967.4	c.3073A>G	p.Thr1025Ala	missense_variant	21/21	2	NM_006218.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23592320, 26453385, 16764926, 22997091, 19903786, 23982433, 34519764, 34858176, 35127508, 31217897, 22729224) -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Mar 03, 2022	This variant has been reported in multiple cancer types and once in the literature in an individual with megalencephaly-capillary malformation (PMID: 22729224, PMID: 23982433). The p.Thr1025Ala variant substitute a threonine with an alanine in the kinase domain of the PIK3CA protein. Variants in this domain are typically activating (PMID: 18268322). This variant has also been observed in patient databases among individuals with cancer or PROS disorder, consisting of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi. -

PIK3CA related overgrowth syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Sep 07, 2023

The PIK3CA c.3073A>G (p.Thr1025Ala) was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with capillary malformations (Rivière JB et al., PMID: 22729224; Mirzaa GM et al., PMID: 23592320; Mirzaa G et al., PMID: 27631024). This variant has been reported in the ClinVar database as a somatic pathogenic variant by multiple submitters and a germline likely pathogenic variant by one submitter (ClinVar ID: 45467). Additionally, it has been reported as a somatic variant in multiple cases in the cancer database cBioPortal. This variant is absent from the general population (gnomAD v3.1.2), indicating it is not a common variant. Another variant in the same codon, c.3074C>G (p.Thr1025Ser), has been reported in multiple cancer cases (Dhami J et al., PMID: 29588307; Gymnopoulos M et al., PMID: 17376864; ClinVar ID: 495324). The PIK3CA c.3073A>G (p.Thr1025Ala) variant resides within a catalytic domain, PI3Kc_IA_alpha, amino acids 695-1064, of PIK3CA that is defined as a critical functional domain (Zhao L et al., PMID: 18268322; Samuels Y et al., PMID: 15016963; Lai et al., PMID: 35997716). However, functional studies that correlate with the impact of this variant on PIK3CA function is lacking. The PIK3CA gene is defined by ClinGen's Brain Malformation expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Lai et al, PMID: 35997716). A large number of PI3K/AKT pathway inhibitors are currently under clinical study in both PROS disorders and cancer (Jin N et al., PMID: 34779417; Venot Q et al., PMID: 29899452; Parker VER et al., PMID: 30270358). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the PIK3CA c.3073A>G (p.Thr1025Ala) variant is classified as likely pathogenic. -

Non-small cell lung carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 10, 2011

The Thr1025Ala variant has been reported in the literature as a somatic change in several different tumor types (endometrium, thyroid, large intestine, pituitary, lung carcinoma; COSMIC). Somatic PIK3CA variants have been identified in up to 4% of cases of lung cancer (Samuels 2004). -

CLOVES syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Aldo Moro University of Bari

Jun 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.88	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.59
Sift	Benign	0.12	T
Sift4G	Benign	0.12	T
Polyphen		0.85	P
Vest4		0.66
MutPred		0.51		Loss of phosphorylation at T1025 (P = 0.039);
MVP		0.95
MPC		2.6
ClinPred		0.90	D
GERP RS		6.1
Varity_R		0.63
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397517202; hg19: chr3-178952018; COSMIC: COSV55873252; COSMIC: COSV55873252;